Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 9; pp. 1517 - 1521
• Main Authors: Sznaidman, Marcos L., Haffner, Curt D., Maloney, Patrick R., Fivush, Adam, Chao, Esther, Goreham, Donna, Sierra, Michael L., LeGrumelec, Christelle, Xu, H.Eric, Montana, Valerie G., Lambert, Millard H., Willson, Timothy M., Oliver, William R., Sternbach, Daniel D.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05-05-2003; Elsevier
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Combinatorial Chemistry Techniques; General and cellular metabolism. Vitamins; Humans; Medical sciences; Mice; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Cytoplasmic and Nuclear - agonists; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Transcription Factors - agonists; Transcriptional Activation; Sulfur nitrogen heterocycle; Agonist; Five membered ring; PPAR-β receptor; Thiazole derivatives; Monkey; Combinatorial chemistry; Selectivity; In vitro; Modeling; Vertebrata; Mammalia; Structure activity relation; Carboxylic acid; Animal; Chemical compound library; Molecular model; Primates; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00207-5

We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to
7k (GW501516) and
7l (GW0742), which shows an EC
50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to
7k (GW501516) and
7l (GW0742), which shows an EC
50 of 1.1 nM against PPARδ with 1000 fold selectivity over the other human subtypes.